Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers.
Ivabradine, 7,8-dimethoxy-3-(3-[[(1S)(4,5-dimethoxybenzocyclobutan-1-yl)methyl]-methylamino]propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one, with a formula of C27H36N2O5, can be represented by the following general formula.

Ivabradine is the first pure heart rate-lowering agent and acts by selective inhibition of the cardiac pacemaker IF current that controls the spontaneous diastolic depolarization in the sinus node and regulates heart rate. Ivabradine's effects are selective to the sinus node and the new agent has no effect on intracardiac conduction, myocardial contractility or ventricular repolarization. Unlike beta-blockers, the most common current treatment for angina, ivabradine is free from sexual disturbances, respiratory side effects caused by constriction or spasm of the airways, bradycardia or rebound phenomena. Now that it is generally believed that heart rate-lowering is an important way of prevention and treatment of angina, this product has opened up a promising new way for the treatment of angina. It is one of the most significant advances in the past 20 years in the treatment of cardiovascular disease.
This invention provides an effective and significant, dose-dependent reduction in heart rate, which is also reflected in a reduction in the rate pressure product leading to a myocardial oxygen consumption. A large clinical program including almost 5000 patients has demonstrated the efficacy and tolerability of ivabradine. The antiangina and anti-ischemic efficacy of ivabradine was evaluated using a standardized exercise tolerance test in four double-blind randomized trials (two versus placebo, and one each versus the beta-blocker atenolol and the calcium channel blocker amlodipine) involving 3222 patients with chronic stable angina. Ivabradine (5 mg and 7.5 mg twice daily) was associated with a significant decrease in angina attacks, and the twice-daily dosage regimen provided uniform efficacy over 24 hours. A sustained reduction in heart rate was demonstrated in patients for at least one year (n=713) and no rebound effect occurred following the withdrawal of treatment. Moreover, no influence on glucose or lipid metabolism was observed.
At present, the rapid release preparations of ivabradine hydrochloride are for marketing. Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hour under fasting condition. Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady state is close to 100 L in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng/ml (CV=29%), and the average plasma concentration is 10 ng/ml (CV=38%) at steady state. Ivabradine is extensively metabolized by the liver and the gut by oxidation through cytochrome P450 3A4 (CYP3A4) only. The major active metabolite is an N-demethylated derivative. Ivabradine is eliminated with a main half-life of 2 hours (70˜75% of the AUC) in plasma and an effective half-life of 11 hours. The total clearance is about 400 ml/min and the renal clearance is about 70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an oral dose is excreted unmetabolized in urine.
The kinetics of ivabradine is linear over an oral dose range of 0.5 mg˜24 mg. The heart rate decreases almost linearly with increasing ivabradine and its main metabolite plasma concentration for doses of up to 15˜20 mg twice daily. At high doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations. When ivabradine is given in combination with strong CYP3A4 inhibitors, it may result in an excessive decrease in heart rate, although this risk reduced with moderate CYP3A4 inhibitors.
When the rapid release preparations of ivabradine hydrochloride are used clinically, the following phenomena may occur: the blood medicine concentration increases so fast that the heart rate decreases too fast (heart rate decreases persistently below 50 beats per minute), or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension. When the plasma concentration is too high, there are side effects, while if it is too low, below the therapeutic concentration, there will be no therapeutic effects.
To reduce the peak-valley phenomenon of the blood medicine concentration of ivabradine, which causes a short increase of the blood medicine concentration and rapid elimination of ivabradine, a sustained release preparation of ivabradine or a pharmaceutically acceptable salt thereof is needed clinically.
At present, Chinese Patent No. CN1482901A, the patent related to ivabradine sustained release preparation, discloses a solid pharmaceutical composition of controlled release of ivabradine. This patent relates to a solid pharmaceutical composition which could be obtained by thermoforming, but no specific pharmaceutical preparation is provided. Moreover, hot extrusion forming technology and hot injection molding technology are used in this patent, which are too complex to be applied in industrialization. Besides, while using these two techniques, drugs and excipients have to be heated to 130° C., which will influence the stability of the drug.
The inventor has tried to use polymethacrylate Eudragit RL and RS to prepare sustained release skeleton tablets by the conventional methods of granulation compression, but a superior sustained release effect was not achieved. This indicates that the sustained release materials used in Chinese Patent No. CN1482901A and the techniques of hot extrusion forming and hot injection molding must be used together, otherwise, even if using Eudragit RL and RS as skeleton materials, a superior sustained release effect can not be achieved via conventional methods.
After researching a large amount of sustained release materials, it was discovered that using conventional sustained release materials, such as hydropropylmethyl cellulose, ethyl cellulose, sodium alginate, polymethacrylate, polyvinyl alcohol, and conventional preparation methods, such as granulation tableting or direct compression, cannot be used to prepare a sustained release preparation of ivabradine with a superior sustained release effect. However, the inventor has unexpectedly discovered that the polymers of polyoxyethylenes and polyvinyl acetates are appropriate for use as the sustained release skeleton materials of ivabradine or a pharmaceutically acceptable salt thereof, and that the sustained release preparation method of ivabradine or a pharmaceutically acceptable salt thereof can be made by conventional methods, such as granulation compression or direct compression. The product has better stability than the solid pharmaceutical composition in Chinese Patent No. CN 1482901A.